JP2007277096A - Medicine containing phenethyl-nicotinamide derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound useful as an NO-production accelerator and/or eNOS (endothelial NO-synthesizing enzyme) activator. <P>SOLUTION: This phenethyl-nicotinamide derivative which is an active ingredient of a medicine has a blood stream circulation-improving effect by its excellent blood vessel endothelial NO production acceleration and/or eNOS-activation activity, and further has platelet agglutination inhibition, anti-thrombotic effect, anti-proliferation effect, anti-inflammatory effect, etc. The disclosed medicine is useful for improving diseases or pathological states having causes of blood vessel endothelium function failure caused by the reduction of the blood vessel endothelial NO production and/or the reduction of the eNOS function, and especially useful as the treating agent of diseases such as circulation failure, etc., such as peripheral artery obstructive disease (PAOD), arteriosclelosis, ischemic heart failure, etc. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a medicament useful as a vascular endothelial cell-derived nitric oxide (NO) production promoter and / or an endothelial nitric oxide synthase (eNOS) activator. The present invention also relates to a medicament comprising a phenethylnicotinamide derivative as an active ingredient. Furthermore, the present invention relates to a novel phenethylnicotinamide derivative and a salt thereof having a vascular endothelial NO production promoting action and / or an eNOS activating action and useful as a medicament.

NO (nitrogen monoxide) is produced when L-arginine is oxidized to L-citrulline, and the reaction is catalyzed by NO synthase (NOS). Although NO production is observed in various tissues and cell types in the living body, typical cell types that constantly produce and release NO are vascular endothelial cells. It has been reported that NO produced in vascular endothelial cells (vascular endothelial NO) is endothelium-derived vasorelaxation factor (EDRF) [Nature, 1987, 327, 524-526; Proc. Natl. Acad. Sci. USA, 1987, 84, 9265-9269].
Vascular endothelium dysfunction seen in arteriosclerotic diseases such as hyperlipidemia and arteriosclerosis is mainly due to attenuation of endothelium-dependent vasorelaxation and dilatation (EDR) caused by a decrease in NO produced from eNOS. It is said that there is.
In addition, vascular endothelial NO produced by eNOS has not only a vasorelaxant action, but also platelet aggregation inhibition, antithrombotic action, antiproliferative action, anti-inflammatory action, etc. (Ayumi of Medicine 204 (4), 621-625, 2003).
Since NO was found to be the main body of EDRF, and NO was also found to play an important role in systemic circulation control, NO-donating preparations such as nitroglycerin preparations (as circulatory failure drugs) (Nitric acid) has been frequently used clinically. However, the NO-donating preparation has a short duration of action and tends to be resistant to long-term use. In addition, due to poor target organ specificity, systemic blood pressure drop, tachycardia due to blood pressure drop, headache, and dizziness appear as side effects. Excessive NO production is also known to cause cytotoxicity.
Moreover, although the effect of L-arginine, which is a NOS substrate, has been studied in diseases related to NO, it has been reported that the effect of long-term administration of L-arginine is weak and partial [Hypertension, 1994, 23 752-756; Hypertension, 1996, 25, 898-902].

Based on these findings, a compound that promotes spontaneous and sufficient NO production in vascular endothelial cells and / or a compound having an eNOS activation action improves vascular endothelial function, blood flow disorder, arteriosclerosis, high fat It is considered to be an excellent therapeutic agent for diseases such as illness, ischemic heart disease and diseases caused by reduced vascular endothelial function such as circulatory failure in various organs.
HMG-CoA reductase inhibitor (cholesterol synthesis inhibitor) increases the amount of mRNA of eNOS in vascular endothelial cells as a compound having an effect on vascular endothelial NO production or eNOS known so far. Have been reported to promote NO production. In addition, 4-fluoro-N-indan-2-ylbenzamide (Patent Document 1), an indanylamino derivative acylated with a heterocyclic group or aryl (Patent Document 2), acylated with a heterocyclic group or aryl 6,7,8,9-tetrahydro-5H-benzocycloheptylamino derivative (Patent Document 3) and 1,2,3,4-tetrahydronaphthylamine acylated with a heterocyclic group or the like (Patent Document 4) It is disclosed to have an expression enhancing action. In addition, soysterol, pyridoxine, riboflavin, taurine, inositol hexanicotinate and pantethine are also known to promote the synthesis of vascular endothelial nitric oxide and / or maintain and improve endothelial nitric oxide blood levels. (Patent Document 5)
However, the compounds of the present invention are structurally different from these compounds.
On the other hand, the following compounds are known as phenethyl nicotinamide derivatives.
Among the phenethyl nicotinamide derivatives, phenethyl nicotinamide and compounds in which the 2-position of the benzene ring is substituted with chlorine are known as production intermediates (Patent Document 6). However, these compounds have weak potassium channel opening action and weakness. It is also known to have a vasodilatory effect (Non-patent Document 1).
A compound in which the 3 or 4 position of the benzene ring is di-substituted with chlorine (Non-Patent Document 2, CAS Registry Number 489416-65-1) and a compound in which the 3 position is 1-substituted with fluorine (Patent Document 7) , Known as synthetic intermediates or reagents.
A compound in which the 2 and 4 positions of the benzene ring are disubstituted with chlorine and the 5 position on the pyridine ring is substituted with bromine is used as a synthetic intermediate (Patent Document 8) and also in the 2 and 4 positions of the benzene ring. Is a compound (CAS Registry Number 380470-94-0) that is disubstituted with chlorine and substituted at the 6-position on the pyridine ring with chlorine.
However, the above document does not disclose or suggest that the phenethylnicotinamide derivative in which the benzene ring of the present invention is substituted with at least one halogen has a vascular endothelial NO production promoting action and / or an eNOS activating action.

International Publication WO02 / 064146 Brochure International Publication WO02 / 64545 Pamphlet International Publication WO02 / 64546 Pamphlet International Publication WO02 / 64565 Brochure JP2004-115507 JP 7-33729 A JP 61-289087 International Publication WO02 / 18327 Brochure Bioorganic & Medicinal Chemistry Letters, 4 (20), 2485-2488, 1994

  An object of the present invention is to provide a novel vascular endothelial NO production promoter and / or eNOS activator. Another object of the present invention is to provide a pharmaceutical comprising a phenethyl nicotinamide derivative as an active ingredient, a novel phenethyl nicotinamide derivative having a vascular endothelial NO production promoting action and / or an eNOS activating action, and a salt thereof.

（式中の記号は、以下の意味を示す。
Hal：ハロゲン、
R：NO₂、CN、低級アルキル、OH、ハロゲノ低級アルキル、COOH、-O-低級アルキル、-COO-低級アルキル、-CONH₂、-CO-(モノ又はジ低級アルキルアミノ)、又は-低級アルキレン-O-低級アルキル、
R¹：H、ハロゲン、低級アルキル、-O-低級アルキル、-S-低級アルキル、又はハロゲノ低級アルキル、
R²：H、低級アルキル、-低級アルキレン-COOH、-低級アルキレン-CONH₂、又は-低級アルキレン-CO-(モノ又はジ低級アルキルアミノ)、
m：１乃至５の整数、
n:0、又は1 但し、m+n≦5、
X：N、又はN-オキシド。）
また、本発明は、これまで医薬としての用途が知られていなかった下記一般式（I)で示されるフェネチルニコチンアミド誘導体又はその製薬学的に許容される塩を有効成分とする医薬に関する。

（式中の記号は、前記の意味を示す。
但し、２−クロロフェネチル−３−ニコチンアミドを除く。）
更に、本発明は、医薬、殊に血管内皮性NO産生促進剤として有用な新規なフェネチルニコチンアミド誘導体又はその塩に関する。

（式中の記号は、以下の意味を示す。
R^1a：H、低級アルキル、-O-低級アルキル、-S-低級アルキル、又はハロゲノ低級アルキル、
Hal,R, R2及びXは前記の意味を示す。
但し、HalがCl又はFでありかつmが1のときは、nは1を示す。） As a result of intensive studies on a compound having a vascular endothelial NO production promoting action and / or an eNOS activating action, the present inventors have found that a compound in which the benzene ring is substituted with at least one halogen is an excellent vascular endothelial NO. The present invention was completed by finding that it has a production promoting effect.
That is, the present invention relates to a vascular endothelial NO production promotion and / or eNOS activator comprising a phenethylnicotinamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

(The symbols in the formula have the following meanings.
Hal: halogen,
R: NO ₂ , CN, lower alkyl, OH, halogeno lower alkyl, COOH, —O-lower alkyl, —COO-lower alkyl, —CONH ₂ , —CO— (mono or di-lower alkylamino), or —lower alkylene -O-lower alkyl,
R ¹ : H, halogen, lower alkyl, —O-lower alkyl, —S-lower alkyl, or halogeno lower alkyl,
R ² : H, lower alkyl, -lower alkylene-COOH, -lower alkylene-CONH ₂ , or -lower alkylene-CO- (mono or di-lower alkylamino),
m: an integer from 1 to 5,
n: 0 or 1 where m + n ≦ 5,
X: N or N-oxide. )
The present invention also relates to a medicament comprising as an active ingredient a phenethyl nicotinamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, which has not been known to be used as a medicament so far.

(The symbols in the formula have the above meanings.
However, 2-chlorophenethyl-3-nicotinamide is excluded. )
Furthermore, the present invention relates to a novel phenethylnicotinamide derivative or a salt thereof useful as a pharmaceutical, particularly a vascular endothelial NO production promoter.

(The symbols in the formula have the following meanings.
R ^1a : H, lower alkyl, —O-lower alkyl, —S-lower alkyl, or halogeno lower alkyl,
Hal, R, R2 and X have the above meanings.
However, when Hal is Cl or F and m is 1, n represents 1. )

  The phenethylnicotinamide derivative or a salt thereof, which is an active ingredient of the medicament of the present invention, has an excellent blood vessel circulation improvement action by promoting vascular endothelial NO production and / or eNOS activation action, and further suppressing platelet aggregation and antithrombosis It also has effects such as action, antiproliferative action, and anti-inflammatory action. The medicament of the present invention is used to improve diseases or pathological conditions caused by vascular endothelial dysfunction caused by reduced vascular endothelial NO production and / or reduced eNOS function, particularly peripheral arterial occlusion (PAOD), arteries It is useful as a therapeutic agent for diseases such as circulatory failure such as sclerosis and ischemic heart disease. In addition, the pharmaceutical of the present invention can be expected to have little influence on blood pressure and heart rate.

Preferred embodiments of the present invention are shown below.
(1) A phenethylnicotinamide derivative or a salt thereof in which m is an integer of 2 to 5 and n is 0 in the general formula (Ia), and a medicine containing these as an active ingredient, particularly vascular endothelial NO production Facilitating and / or eNOS activator.
(2) A phenethylnicotinamide derivative or a salt thereof, in which m is 2, n is 0, R ^1a is H, and X is N in the general formula (Ia), and a medicament containing these as an active ingredient, And vascular endothelial NO production promoter and / or eNOS activator.
(3) A medicine containing a phenethylnicotinamide derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient prevents peripheral arterial occlusion, arteriosclerosis, or ischemic heart disease An agent that is a therapeutic agent.

Further, the present invention will be described in detail.
“Halogen” includes fluorine, chlorine, bromine or iodine atoms.
In addition, when m shows 2 or more, each halogen may be the same and may differ.
The “lower alkyl” is linear or branched saturated C _1-6 alkyl, preferably methyl, ethyl, isopropyl or hexyl.
The “halogeno lower alkyl” means a group in which any one or more hydrogen atoms of the lower alkyl are substituted with the halogen. Halogeno C _1-3 alkyl is preferable, and trifluoromethyl and trifluoroethyl are more preferable.
The “mono or di-lower alkylamino” is a symmetric or asymmetric amino group in which the hydrogen of the amino group is substituted with 1 or 2 lower alkyl, preferably methylamino or dimethylamino.
The compounds of the present invention also include compounds substituted with a group that forms a prodrug.
Here, examples of the group that forms the prodrug of the present invention include Prog. Med., 5, 2157-2161 (1985) and “Development of Drugs”, Volume 7 (Yodogawa Shoten, 1990), Molecular Design pages 163-198. And the like.

The compounds (I) and (Ia) of the present invention may form an acid addition salt or a salt with a base depending on the kind of the substituent, and as long as such a salt is a pharmaceutically acceptable salt, the present invention Is included. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid, sodium, potassium, magnesium, calcium, aluminum, etc. Inorganic bases, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, ammonium salts, and the like. The present invention also includes various hydrates and solvates and crystalline polymorphs of the compound of the present invention and pharmaceutically acceptable salts thereof.
The compounds of the present invention may have optical isomers (optically active substances, diastereomers, etc.) depending on the type of group. Moreover, this invention compound is a compound which has an amide bond, and a tautomer exists. The present invention includes a separated or a mixture of these isomers.
The present invention also includes compounds obtained by labeling the compounds of the present invention with radioisotopes.

(Production method)
The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic skeleton or the type of substituent.
In this case, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the raw material or intermediate stage. There is. Examples of such functional groups include amino groups, hydroxyl groups, carboxy groups, and the like. For example, Greene and Wuts, Protective Groups in Organic Synthesis (Third Edition). The protecting groups described can be used, and these may be appropriately selected according to the reaction conditions. In such a method, a desired compound can be obtained by carrying out the reaction by introducing the protecting group and then removing the protecting group as necessary.
Hereafter, the typical manufacturing method of this invention compound is demonstrated. The production method of the present invention is not limited to the examples illustrated below.
The symbols in the following sentences are as follows.

（式中の記号は前記の通りである。以下同様）
本発明化合物（Ｉ）は、対応するカルボン酸化合物（ＩＩ）と式（ＩＩＩ）で示されるフェネチルアミンとを公知の方法（例えばM. Bodanszky、Peptide Chemistry、ｐ５５−７３（１９８８）、泉屋信夫ら，ペプチド合成の基礎と実験，ｐ８９−１４２，（１９８５）などが参照される）によりアミド化することにより製造できる。なお、XがＮ−オキシドである本発明化合物（Ｉ）は、対応するカルボン酸誘導体（ＩＩ）のＮ−オキシドを用いて製造することができる。
好ましくは、カルボン酸化合物（ＩＩ）を反応性誘導体（例えば酸クロリド、酸ブロミド等の酸ハライド；酸アジド；メタノール、エタノール、ベンジルアルコール、置換していてもよいフェノール、Ｎ−ヒドロキシスクシンイミド等を用いて調整できる活性エステル；対称酸無水物；アルキル炭酸；ｐ−トルエンスルホン酸等との混合酸無水物等）に変換した後、化合物（ＩＩＩ）と反応させることにより行うことができる。カルボン酸の反応性誘導体を用いる場合、塩基（水酸化ナトリウム等の無機塩基、又はトリエチルアミン（TEA）、ジイソプロピルエチルアミン、ピリジン等の有機塩基）を添加することが好ましい。更にアミド化はカルボン酸を縮合剤（１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド（WSC）、１，１’−カルボニルビス−１−１Ｈ−イミダゾール（CDI）等）の存在下に反応させることによって行うこともできる。その際1-ヒドロキシベンゾトリアゾール（HOBt）等の添加剤を加えてもよい。
反応温度は、原料化合物に応じて適宜選択できる。溶媒は不活性溶媒、例えばベンゼン、トルエン等の芳香族炭化水素系溶媒、１、４−ジオキサン、テトラヒドロフラン（ＴＨＦ）などのエーテル系の溶媒、Ｎ、Ｎ−ジメチルホルムアミド（ＤＭＦ）等が挙げられ、原料化合物の種類等に従い適宜選択され、単独、或いは２種以上混合して用いられる。 First production method (amidation)

(The symbols in the formula are as described above. The same applies hereinafter.)
The compound (I) of the present invention is obtained by reacting the corresponding carboxylic acid compound (II) and phenethylamine represented by the formula (III) by a known method (for example, M. Bodanszky, Peptide Chemistry, p55-73 (1988), Nobuo Izumiya et al., Peptide synthesis basis and experiment, p89-142, (1985) and the like). In addition, this invention compound (I) whose X is N-oxide can be manufactured using N-oxide of a corresponding carboxylic acid derivative (II).
Preferably, carboxylic acid compound (II) is used as a reactive derivative (for example, acid halide such as acid chloride or acid bromide; acid azide; methanol, ethanol, benzyl alcohol, optionally substituted phenol, N-hydroxysuccinimide or the like). Active ester, symmetric acid anhydride, alkyl carbonate, mixed acid anhydride with p-toluenesulfonic acid, etc.), and then reacted with compound (III). When a reactive derivative of carboxylic acid is used, it is preferable to add a base (an inorganic base such as sodium hydroxide or an organic base such as triethylamine (TEA), diisopropylethylamine, or pyridine). Further, amidation is carried out in the presence of a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1′-carbonylbis-l-1H-imidazole (CDI), etc.). It can also be performed by reacting. At that time, an additive such as 1-hydroxybenzotriazole (HOBt) may be added.
The reaction temperature can be appropriately selected depending on the raw material compound. Examples of the solvent include inert solvents such as aromatic hydrocarbon solvents such as benzene and toluene, ether solvents such as 1,4-dioxane and tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and the like. It is appropriately selected according to the type of raw material compound and the like, and is used alone or in combination of two or more.

（Ｙはハロゲンまたはスルホネート等の脱離基、Ｒ^2aは低級アルキル、−Ｚ−ＣＯＯＲｂ（Ｒ^bは低級アルキル、Ｚは低級アルキレン基）を示す。）
本発明化合物中、式（Ｉ）で示される化合物のうち、Ｒ²が低級アルキル又は−Ｚ−ＣＯＯＲ^bで置換されたアミド化合物（Ｉｂ）は、対応するＲ²がＨのアミド化合物（ＩＶ）及び式（Ｖ）で示されるアルキル化剤と反応させる常法のＮ−アルキル化反応によって製造できる。
反応は適当な不活性溶媒（好ましくは、ＴＨＦなどのエーテル系溶媒あるいはＤＭＦ）中、反応対応量の化合物（ＩＶ）と化合物（Ｖ）あるいはいずれか一方の過剰量を用い、必要ならば酸補足剤として、例えば水素化ナトリウム、カリウム ｔｅｒｔ−ブトキシド、炭酸カリウム、ＴＥＡ等の無機または有機塩基を加え、冷却下、室温下又は加熱下に実施するのが有利である。 Second production method (alkylation)

(Y represents a leaving group such as halogen or sulfonate, R ^2a represents lower alkyl, and —Z—COORb (R ^b represents lower alkyl, Z represents lower alkylene group).
In the present invention compounds, among the compounds of formula (I), amide compound R ² is substituted by a lower alkyl or -Z-COOR ^b (Ib) is the corresponding R ² is an amide compound of the H (IV) And a conventional N-alkylation reaction in which the compound is reacted with an alkylating agent represented by the formula (V).
In the reaction, an appropriate inert solvent (preferably an ether solvent such as THF or DMF) is used in an amount corresponding to compound (IV) and / or compound (V) in an amount corresponding to the reaction, and if necessary, supplemented with an acid. As an agent, for example, an inorganic or organic base such as sodium hydride, potassium tert-butoxide, potassium carbonate, TEA or the like is added, and the reaction is advantageously carried out under cooling, at room temperature or under heating.

（式中の記号は前記の通りである。）
本発明化合物中、式（Ｉ）で示される化合物のうち、Ｒ²が低級アルキレン-COOHで置換されたアミド化合物（ＶＩＩ）は、対応するエステル化合物（ＶＩ）のケン化によって製造できる。
反応は常法を適用して行うことができ、適当な不活性溶媒（好ましくは、メタノール、エタノールなどのアルコール溶媒）中、適当な無機塩基、例えば水酸化ナトリウム、水酸化カリウム、水酸化リチウム等を添加し、冷却下、室温下又は加熱下に実施するのが有利である。 Third production method (saponification)

(The symbols in the formula are as described above.)
Among the compounds of the present invention, among the compounds represented by the formula (I), the amide compound (VII) in which R ² is substituted with lower alkylene-COOH can be produced by saponification of the corresponding ester compound (VI).
The reaction can be carried out by applying a conventional method, and in a suitable inert solvent (preferably an alcohol solvent such as methanol or ethanol), a suitable inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. It is advantageous to carry out under cooling, at room temperature or under heating.

（式中、Ｒ³及びＲ⁴は低級アルキルを意味する。）
本発明化合物中、式（Ｉ）で示される化合物のうち、Ｒ²が低級アルキレン−ＣＯＮＨ₂、低級アルキレン−ＣＯ−モノ又はジ低級アルキルアミノで置換されたアミド化合物（Ｘ）は、対応するカルボン酸化合物（ＶＩＩＩ）又はその活性化体と式（ＩＸ）で示されるアンモニア又はモノ−若しくはジ−低級アルキルアミンとを、第１製法と同様にアミド化（アンモニアの時はアンモノリシス）することにより製造できる。 Fourth production method (amidation)

(In the formula, R ³ and R ⁴ represent lower alkyl.)
Among the compounds of the present invention, among the compounds represented by the formula (I), the amide compound (X) in which R ² is substituted with lower alkylene-CONH ₂ , lower alkylene-CO-mono or di-lower alkylamino is a corresponding carboxylic acid. Produced by amidating acid compound (VIII) or an activated form thereof with ammonia or mono- or di-lower alkylamine represented by formula (IX) (ammonolysis in the case of ammonia) in the same manner as in the first production method. it can.

The compound of the present invention is isolated and purified as a free compound, a pharmaceutically acceptable salt, hydrate, solvate, or crystalline polymorphic substance. The pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting it to a conventional salt formation reaction.
Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
Various isomers can be separated by selecting an appropriate raw material compound or utilizing the difference in physicochemical properties between isomers. For example, optical isomers can be selected by selecting appropriate raw materials or by optical resolution of racemates (for example, diastereomeric salts with general optically active bases or acids, optical resolution, chiral columns, etc. Can be led to a stereochemically pure isomer.
As described above, the compounds shown in the following table can be obtained in the same manner as in the present production method in addition to the example compounds described later. In addition, some compounds in the table below were obtained.
The active ingredient of the present invention as well as the compound of the present invention or a pharmaceutically acceptable salt thereof can be used alone or as a medicament, but usually one or two or more active ingredients are used as a pharmaceutical carrier usually used in the art, It can be prepared by a commonly used method using an excipient or the like. Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, one or more active ingredients are combined with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, And / or mixed with magnesium aluminate metasilicate. The composition contains additives other than inert diluents, for example, lubricants such as magnesium stearate, disintegrants such as calcium calcium glycolate, stabilizers, and solubilizing agents according to a conventional method. May be. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solution or suspension include distilled water for injection or physiological saline. Examples of the water-insoluble solution or suspension include vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, or polysorbate 80 (Pharmacopeia name). Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
A transmucosal agent such as a nasal agent is used in a solid, liquid, or semi-solid state, and can be produced according to a conventionally known method. For example, known pH adjusters, preservatives, thickeners and excipients are appropriately added to form a solid, liquid or semi-solid. The nasal agent is administered using a normal spray device, a nasal container, a tube, or an intranasal insertion device.
Usually, in the case of oral administration, the daily dose is about 0.001 to 1000 mg, preferably 0.1 to 300 mg, more preferably 0.1 to 100 mg, which is administered once or divided into 2 to 4 times. . When administered intravenously, the daily dose is suitably about 0.0001 to 500 mg, and is administered once a day or divided into multiple times. As a transmucosal agent, about 0.001 to 500 mg is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

[Example]
Hereinafter, the present invention will be described in more detail based on examples. The compounds of the present invention are not limited to the compounds described in the following examples. Moreover, the manufacturing method of a raw material compound is shown in a reference example.
Abbreviations in the specification are as follows.
FAB-MS: Measured by fast atom bombardment ionization mass spectrometry; EI-MS; Measured by electron impact ionization mass spectrometry; NMR (DMSO): NMR (DMSO-d ₆ , TMS internal standard) characteristic peak δppm ; Me: methyl; null: not present; Salt: salt

Reference Example 1 2- (4-Bromo-2-chlorophenyl) ethylamine 1.7 ml of thionyl chloride was added to a solution of 2.6 g of (4-bromo-2-chlorophenyl) methanol in 30 ml of chloroform at room temperature and stirred for 1 hour. The solvent was distilled off under reduced pressure to obtain 2.4 g of a residue. The obtained residue was used for the next reaction as it was.
To a 30 ml solution of the residue in acetonitrile, 2.4 g of potassium cyanide and 3.4 g of 18-crown-6-ether were sequentially added at room temperature, followed by stirring at 80 ° C. overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; ethyl acetate: hexane) to give a pale yellow oil. The obtained pale yellow oil was used in the next reaction as it was without further purification.
To a 20 ml THF solution of a pale yellow oil was added 20 ml borane-THF complex (1M THF solution), and the mixture was heated to reflux for 4 hours. After cooling to room temperature, 1M aqueous hydrochloric acid solution was added and the mixture was further heated to reflux for 1 hour. After cooling to room temperature again, 1M aqueous sodium hydroxide solution was added to make the reaction system basic, and the mixture was extracted with ethyl acetate. The organic layer was extracted with a 1M aqueous hydrochloric acid solution, made basic with a 1M aqueous sodium hydroxide solution, and then extracted again with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 772 mg of 2- (4-bromo-2-chlorophenyl) ethylamine as a pale yellow oil.
FAB-MS: 234, 236 (M + 1)

Reference Example 2 2- [2-Chloro-5- (trifluoromethyl) phenyl] ethylamine [2-Chloro-5- (trifluoromethyl) phenyl] acetonitrile 1.66 ml of borane-dimethyl sulfide complex was added to 787 mg of THF 7 ml solution. Heated to reflux for 6 hours. After cooling to room temperature, 4M aqueous hydrochloric acid solution was added and the mixture was further heated to reflux for 1 hour. After cooling to room temperature again, the aqueous layer was washed with diethyl ether, 1M aqueous sodium hydroxide solution was added to make the aqueous layer basic, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 682 mg of 2- [2-chloro-5- (trifluoromethyl) phenyl] ethylamine (Reference Example 2-1) as colorless. Obtained as an oil.
In the same manner, the compounds shown in (Table 1) were produced.

Reference Example 3 2- (4-Bromo-2-fluorophenyl) ethylamine To a solution of 1.0 g of 4-bromo-2-fluorobenzyl chloride in 30 ml of acetonitrile was added sequentially 874 mg of potassium cyanide and 1.4 g of 18-crown-6-ether at room temperature. Stir at 60 ° C. overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue 864 mg was directly used in the next reaction.
To a solution of 864 mg of the residue in 10 ml of THF, 20 ml of borane-THF complex (1M THF solution) was added and heated under reflux for 2 hours. After cooling to room temperature, 1M aqueous hydrochloric acid solution was added and the mixture was further heated to reflux for 1 hour. After cooling to room temperature again, 1M aqueous sodium hydroxide solution was added to make the reaction system basic, and the mixture was extracted with ethyl acetate. The organic layer was extracted with a 1M aqueous hydrochloric acid solution, made basic with a 1M aqueous sodium hydroxide solution, and then extracted again with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 388 mg of 2- (4-bromo-2-fluorophenyl) ethylamine as a pale yellow oil.
FAB-MS: 218, 220 (M + 1)

Reference Example 4 (4-Chloro-2-methoxyphenyl) acetonitrile (4-Chloro-2-methoxyphenyl) Methanol (5.3 g) in 100 ml of THF was added with 2.7 ml of thionyl chloride under ice-cooling and stirred for 30 minutes. After raising the temperature to room temperature, the solvent was distilled off under reduced pressure to obtain the residue as a colorless oil. The obtained residue was used for the next reaction as it was.
To a solution of the residue in 100 ml of acetonitrile, 3.0 g of potassium cyanide and 12.3 g of 18-crown-6-ether were sequentially added at room temperature, followed by stirring at 60 ° C. overnight. After cooling to room temperature, the reaction solution was distilled off under reduced pressure to some extent. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane = 1: 2) to obtain 3.6 g of (4-chloro-2-methoxyphenyl) acetonitrile as a pale yellow solid.
FAB-MS: 180 (M-1)

Reference Example 5 2- (4-Chloro-4-methoxyphenyl) ethylamine (4-chloro-2-methoxyphenyl) acetonitrile (3.6 g), Raney nickel (about 10 g), a 30% aqueous ammonia solution and ethanol were mixed in a hydrogen stream for 6 hours. . After filtration using Celite, the solvent was evaporated under reduced pressure to obtain 3.5 g of 2- (4-chloro-4-methoxyphenyl) ethylamine as a colorless oil.
ES-MS: 186, 188 (M + 1)

Production Example 1 N- [2- (2-Chlorophenyl) ethyl] nicotinamide hydrochloride 890 mg of nicotinic acid chloride hydrochloride was gradually added to a mixture of 778 mg of 2- (2-chlorophenyl) ethylamine in 4 ml of pyridine and 4 ml of 1,4-dioxane. And stirred at 80 ° C. for 2 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was made into hydrochloride using 4M hydrochloric acid ethyl acetate solution, and the crystals precipitated with methanol-ethyl acetate were collected by filtration to give N- [2- (2-chlorophenyl) ethyl] nicotinamide hydrochloride. 1.36 g was obtained as a white solid.

Production Examples 2 to 4 In the same manner as in Production Example 1, the compounds of Production Examples 2 to 4 shown in the following (Table 2) were produced.
Production Examples 5 and 6 In the same manner as in Example 51 described below, the compounds of Production Examples 5 and 6 shown in the following (Table 2) were produced.

Example 1 In the same manner as in Production Example 1, the compound of Example 1 shown in the following (Table 3) was produced.

Example 2 N- [2- (2-Chloro-4-fluorophenyl) ethyl] nicotinamide hydrochloride (1) (2-chloro-4-fluorophenyl) acetonitrile 10.2 g of borane-dimethylsulfide complex was added to 100 ml of THF solution. 17 ml was added and heated to reflux overnight. After cooling to room temperature, 4M hydrochloric acid ethyl acetate solution was added and stirred for 2 hours. After distilling off the solvent under reduced pressure, 1M aqueous hydrochloric acid solution was added and washed with ethyl acetate. The aqueous layer was made basic by adding 1M aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 7.35 g of 2- (2-chloro-4-fluorophenyl) ethylamine (Reference Example 2-9).
(2) To a mixed solution of 2- (2-chloro-4-fluorophenyl) ethylamine 1.05 g of pyridine 3 ml and 1,4-dioxane 4 ml, nicotinic acid chloride hydrochloride 1.2 g was gradually added and stirred at 80 ° C. for 1 hour. . After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was converted into a hydrochloride using 4M hydrochloric acid ethyl acetate solution, and crystals precipitated with ethanol-ethyl acetate were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain 1.18 g of N- [2- (2-chloro-4-fluorophenyl) ethyl] nicotinamide hydrochloride as a white solid.

Examples 3 to 39 The compounds of Examples 3 to 39 shown in the following (Table 3) to (Table 6) were produced in the same manner as in Example 2 (2).

Example 40 N- [2- (2,3,4-trifluorophenyl) ethyl] nicotinamide hydrochloride (2,3,4-trifluorophenyl) acetonitrile (428 mg) in THF (5 ml) and borane-dimethyl sulfide complex (1.19 ml) And heated to reflux for 6 hours. After cooling to room temperature, 4M aqueous hydrochloric acid solution was added, and the mixture was further heated to reflux for 1 hr. After cooling to room temperature again, the aqueous layer was washed with diethyl ether. A 1 M aqueous sodium hydroxide solution was added to make the aqueous layer basic, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue 270 mg was used as it was in the next reaction.
329 mg of nicotinic acid chloride hydrochloride was added to a mixture of 270 mg of 270 mg of pyridine and 6.2 ml of 1,4-dioxane, and the mixture was stirred at 80 ° C. for 30 minutes. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was made into hydrochloride using 4M hydrochloric acid ethyl acetate solution, and the crystals precipitated with ethanol were collected by filtration, and N- [2- (2,3,4-trifluorophenyl) ethyl] nicotine was collected. 235 mg of amide hydrochloride was obtained as a white solid.

Example 41 In the same manner as in Example 40, the compound of Example 41 shown below (Table 6) was produced.

Example 42 N- [2- (2-Chloro-4-fluorophenyl) ethyl] -2-methylnicotinamide hydrochloride To a solution of 206 mg of 2-methylnicotinic acid in 4 ml of DMF, 243 mg of HOBt and 575 mg of WSC hydrochloride were successively added at room temperature. It was. After 30 minutes, 347 mg of 2- (2-chloro-4-fluorophenyl) ethylamine was added, and the mixture was further stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate), converted into hydrochloride using 4M hydrochloric acid ethyl acetate solution, and the crystals precipitated with ethanol-diethyl ether were collected by filtration and filtered with N- [2 371 mg of-(2-chloro-4-fluorophenyl) ethyl] -2-methylnicotinamide hydrochloride was obtained as a white solid.

Examples 43 to 50 In the same manner as in Example 42, compounds of Examples 43 to 50 shown in the following (Table 7) were synthesized.

Example 51 N- [2- (2,4-dichlorophenyl) ethyl] -2-methoxynicotinamide To a solution of 1.0 g of 2-methoxynicotinic acid in 20 ml of THF, 2.73 ml of TEA, 1.87 ml of ethyl chloroformate and 2- ( 2,4-Dichlorophenyl) ethylamine (0.98 ml) was sequentially added and stirred for 5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. From the obtained residue, crystals precipitated with ethyl acetate-hexane were collected by filtration to obtain 1.25 g of N- [2- (2,4-dichlorophenyl) ethyl] -2-methoxynicotinamide as a white solid.

Examples 52 to 55 In the same manner as in Example 51, the compounds of Examples 52 to 55 shown in the following (Table 8) were synthesized.

Example 56 N- [2- (2,4-Dichlorophenyl) ethyl] nicotinamide 1-oxide
NMR (DMSO): 2.96 (2H, t, J = 6.8Hz), 3.51 (2H, dt, J = 6.8, 6.8Hz), 7.35-7.39 (2H), 7.51 (1H, dd, J = 8.4, 6.4Hz) ), 7.59 (1H, s), 7.66 (1H, d, J = 8.4Hz), 8.34 (1H, d, J = 6.4Hz), 8.51 (1H), 8.84 (1H).
ES-MS: 311, 313, 315 (M + 1)

Example 57 In the same manner as in Example 51, the compound of Example 57 shown in the following (Table 8) was synthesized.

Example 58 [[2- (2,4-Dichlorophenyl) ethyl] (pyridin-3-ylcarbonyl) amino] acetic acid N- [2- (2,4-dichlorophenyl) ethyl] nicotinamide 2.9 g in a 50 ml THF solution 520 mg of 60% oily sodium hydride was gradually added with stirring on ice. After 30 minutes, the temperature was raised to room temperature, and 1.6 ml of ethyl bromoacetate was added, followed by further stirring for 2 hours. Ammonium chloride and 1M aqueous hydrochloric acid solution were sequentially added to the reaction solution, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; ethyl acetate: hexane) to obtain 873 mg of a pale yellow oil. The obtained pale yellow oil was used in the next reaction as it was without further purification.
To a solution of 673 mg of pale yellow oil in 15 ml of methanol was added 3.4 ml of 1M aqueous sodium hydroxide solution at room temperature, and the mixture was stirred for 1 hour. To the reaction solution was added 3.4 ml of 1M aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. From the obtained residue, crystals precipitated with ethyl acetate-hexane were collected by filtration to obtain 562 mg of [[2- (2,4-dichlorophenyl) ethyl] (pyridin-3-ylcarbonyl) amino] acetic acid as a white solid. It was.

Example 59 N- (2-amino-2-oxoethyl) -N- [2- (2,4-dichlorophenyl) ethyl] nicotinamide [[2- (2,4-dichlorophenyl) ethyl] (pyridin-3-yl To a solution of carbonyl) amino] acetic acid (331 mg) in DMF (6 ml), HOBt (153 mg) and WSC hydrochloride (360 mg) were sequentially added at room temperature. After 30 minutes, about 500 mg of ammonium carbonate was added, and the mixture was further stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. From the obtained residue, crystals precipitated with ethyl acetate-hexane were collected by filtration, and 310 mg of N- (2-amino-2-oxoethyl) -N- [2- (2,4-dichlorophenyl) ethyl] nicotinamide was added. Obtained as a white solid.

Examples 60 and 61 In the same manner as in Example 59, the compounds of Examples 60 and 61 shown below (Table 8) were synthesized.

Example 62 N- [2- (2-Chloro-4-fluorophenyl) ethyl] -N-methylnicotinamide hydrobromide 1.0 g of N- [2- (2,4-dichlorophenyl) ethyl] nicotinamide To 15 ml of THF, 203 mg of 60% oily sodium hydride was gradually added with stirring under ice cooling. After 1 hour, 0.57 ml of methyl iodide was added, and the mixture was immediately warmed to room temperature and further stirred for 1 hour. Ammonium chloride and 1M aqueous hydrochloric acid solution were sequentially added to the reaction solution, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 2: 1), converted into a hydrobromide salt using a hydrobromic acid ethanol solution, and then precipitated with ethanol-diethyl ether. The crystals were collected by filtration to obtain 1.23 g of N- [2- (2-chloro-4-fluorophenyl) ethyl] -N-methylnicotinamide hydrobromide as a white solid.

Example 63 N- [2- (3-Bromo-4-methoxyphenyl) ethyl] nicotinamide Nicotinic acid chloride hydrochloride In a solution of 5.3 mg of THF in 1 mL of THF, 6.9 mg of 2- (3-bromo-4-methoxyphenyl) ethylamine was added. After adding 0.06 mL of N-methyl-2-pyrrolidinone solution and further adding 21 mg of PS-diisopropylethylamine (Argonaut Technologies, 3.57 mmol / g), the mixture was stirred at room temperature for 1 day. After adding 27 mg of PS-trisamine (Argonaut Technologies, 3.38 mmol / g) and 34 mg of PS-isocyanate (Argonaut Technologies, 1.47 mmol / g) to the reaction solution, the mixture was stirred at room temperature for 2 hours. The solution obtained by filtering the reaction solution was subjected to HPLC (column: CAPCELLPAK C18 AQ 5 μM 30 x 50 mm (manufactured by Shiseido); solvent: MeOH / 0.1% HCOOH-H ₂ O = 10/90 (0 min) -10 / 90 (1 min)-100/0 (9 min) -100/0 (12 min); flow rate 30 mL / min), and purification was performed, and N- [2- (3-bromo-4-methoxyphenyl) was obtained. ) Ethyl] nicotinamide was obtained quantitatively.

Example 64 The compound of Example 64 shown in the postscript (Table 8) was manufactured like Example 2 (2).

  The compounds and physical property values obtained by the above production examples and examples are shown in Tables 2 to 8 below.

Moreover, according to the said Example, the compound of following Table 9 is compoundable.

この結果、本発明に用いられる化合物はNO産生促進活性を有することが確認された。 The NO production promoting activity, eNOS activation activity and blood flow increasing action of the compound of the present invention were confirmed by the following test methods.
Experimental example 1: Measurement of culture supernatant NOx amount Human aorta-derived vascular endothelial cells (HAEC, manufactured by Clonetics) were cultured to collagen type IV-treated 24-well plate (manufactured by Iwaki Co., Ltd.) until confluent, and then the medium was serum-free medium The culture was continued for 16 hours. After removing the medium, the cells were treated with a serum-free medium containing the test compound for 30 minutes. The amount of NO released from the cells was calculated by measuring the amount of NOx (NO ₂ ⁻ , NO ₃ ⁻ ) in the culture supernatant. The amounts of NO ₂ ⁻ and NO ₃ ⁻ were measured using a nitric oxide analysis system (Eicom) according to the attached method.
Results: The NOx increase rate in the culture supernatant is shown in the table below as a relative ratio to the solvent addition (0.1% DMSO) group.

As a result, it was confirmed that the compound used in the present invention has NO production promoting activity.

Experimental example 2: Measurement of intracellular eNOS activity with ³ H-arginine
^The measurement of intracellular eNOS activity by ³ H-arginine followed the report of Rajesh KD et al. (Rajesh KD et al., Hypertension, 1993, 21, 939-94). Human aorta-derived vascular endothelial cells (HAEC, manufactured by Clonetics) were cultured until they became confluent in collagen type IV-treated 24-well plates (manufactured by Iwaki Co., Ltd.), then the medium was changed to serum-free medium without L-Arg, and 16 hours The culture was continued. After removing the medium, ³ H-Arg (final concentration 1.5 μCi / mL), modified HEPES solution containing the test compound (25 mM Hepes (pH 7.4), 140 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl2, 1.0 mM MgCl2, The cells were treated with 5.0 mM glucose). Ice-cold 1.3N TCA was added at 400 ul / well to stop the reaction, and the cells were disrupted by freeze-thawing. The cell lysate is treated with ether, Stop buffer (200 mM Hepes (pH 5.5), 20 mM EDTA) and Dowex resin (Bio-Rad) are added and mixed, then Dowex resin is removed by filtration, and 3H-Citrullin is liquid scintillated. Measured with a counter.

Experimental Example 3 Increased hindlimb blood flow in anesthetized rats For the production examples and examples of the present invention, the increased hindlimb blood flow in Pentobarbital anesthetized rats was confirmed by the following test method.
Wistar male rats (Japan SLC) were used. The test compound was orally administered, and 2 hours later, Pentobarbital Na 60 mg / kg was intraperitoneally administered and anesthetized. The hindlimb blood flow was measured using a laser blood flow imaging device (PIM II; Integral).
As a result of the above test, the blood flow improving effect of the compound of the present invention was confirmed.

Claims (3)

Vascular endothelial nitric oxide production promotion and / or endothelial nitric oxide synthase activator comprising a phenethylnicotinamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient .

(The symbols in the formula have the following meanings.
Hal: halogen,
R: NO ₂ , CN, lower alkyl, OH, halogeno lower alkyl, COOH, —O-lower alkyl, —COO-lower alkyl, —CONH ₂ , —CO— (mono or di-lower alkylamino), or —lower alkylene -O-lower alkyl,
R ¹ : H, halogen, lower alkyl, —O-lower alkyl, —S-lower alkyl, or halogeno lower alkyl,
R ² : H, lower alkyl, -lower alkylene-COOH, -lower alkylene-CONH ₂ , or -lower alkylene-CO- (mono or di-lower alkylamino),
m: an integer from 1 to 5,
n: 0 or 1 where m + n ≦ 5,
X: N or N-oxide. ) The pharmaceutical which contains the phenethyl nicotinamide derivative or its pharmaceutically acceptable salt shown by the following general formula (I) as an active ingredient.

(The symbols in the formula have the following meanings.
Hal: halogen,
R: NO ₂ , CN, lower alkyl, OH, halogeno lower alkyl, COOH, —O-lower alkyl, —COO-lower alkyl, —CONH ₂ , —CO— (mono or di-lower alkylamino), or —lower alkylene -O-lower alkyl,
R ¹ : H, halogen, lower alkyl, —O-lower alkyl, —S-lower alkyl, or halogeno lower alkyl,
R ² : H, lower alkyl, -lower alkylene-COOH, -lower alkylene-CONH ₂ , or -lower alkylene-CO- (mono or di-lower alkylamino),
m: an integer from 1 to 5,
n: 0 or 1 where m + n ≦ 5,
X: N or N-oxide.
However, 2-chlorophenethyl-3-nicotinamide is excluded. ) A phenethylnicotinamide derivative represented by the following general formula (Ia) or a salt thereof.

(The symbols in the formula have the following meanings.
Hal: halogen,
R: NO ₂ , CN, lower alkyl, OH, halogeno lower alkyl, COOH, —O-lower alkyl, —COO-lower alkyl, —CONH ₂ , —CO— (mono or di-lower alkylamino), or —lower alkylene -O-lower alkyl,
R ^1a : H, lower alkyl, —O-lower alkyl, —S-lower alkyl, or halogeno lower alkyl,
R ² : H, lower alkyl, -lower alkylene-COOH, -lower alkylene-CONH ₂ , or -lower alkylene-CO- (mono or di-lower alkylamino),
m: an integer from 1 to 5,
n: 0 or 1 where m + n ≦ 5,
X: N or N-oxide.
However, when Hal is Cl or F and m is 1, n represents 1. )